Long-lasting forms of synaptic plasticity and memory require de novo protein synthesis. Yet, how learning triggers this process to form memory is unclear. Translin/trax is a candidate to drive this learning-induced memory mechanism by suppressing microRNA-mediated translational silencing at activated synapses. We find that mice lacking translin/trax display defects in synaptic tagging, which requires protein synthesis at activated synapses, and long-term memory. Hippocampal samples harvested from these mice following learning show increases in several disease-related microRNAs targeting the activin A receptor type 1C (ACVR1C), a component of the transforming growth factor-β receptor superfamily. Furthermore, the absence of translin/trax abolishes synaptic upregulation of ACVR1C protein after learning. Finally, synaptic tagging and long-term memory deficits in mice lacking translin/trax are mimicked by ACVR1C inhibition. Thus, we define a new memory mechanism by which learning reverses microRNA-mediated silencing of the novel plasticity protein ACVR1C via translin/trax.

The purpose of this chapter is to highlight the state of progress for phosphodiesterase-4 (PDE4) modulation as a potential therapeutic for psychiatric illness, and to draw attention to particular hurdles and obstacles that must be overcome in future studies to develop PDE4-mediated therapeutics. Pathological and non-pathological related memory loss will be the focus of the chapter; however, we will at times also touch upon other psychiatric illnesses like anxiety and depression. First, we will provide a brief background of PDE4, and the rationale for its extensive study in cognition. Second, we will explore fundamental differences in individual PDE4 subtypes, and then begin to address differences between pathological and non-pathological aging. Alterations of cAMP/PDE4 signaling that occur within normal vs. pathological aging, and the potential for PDE4 modulation to combat these alterations within each context will be described. Finally, we will finish the chapter with obstacles that have hindered the field, and future studies and alternative viewpoints that need to be addressed. Overall, we hope this chapter will demonstrate the incredible complexity of PDE4 signaling in the brain, and will be useful in forming a strategy to develop future PDE4-mediated therapeutics for psychiatric illnesses.

Alterations in cAMP signaling are thought to contribute to neurocognitive and neuropsychiatric disorders. Members of the cAMP-specific phosphodiesterase 4 (PDE4) family, which contains >25 different isoforms, play a key role in determining spatial cAMP degradation so as to orchestrate compartmentalized cAMP signaling in cells. Each isoform binds to a different set of protein complexes through its unique N-terminal domain, thereby leading to targeted degradation of cAMP in specific intracellular compartments. However, the functional role of specific compartmentalized PDE4 isoforms has not been examined in vivo. Here, we show that increasing protein levels of the PDE4A5 isoform in mouse hippocampal excitatory neurons impairs a long-lasting form of hippocampal synaptic plasticity and attenuates hippocampus-dependent long-term memories without affecting anxiety. In contrast, viral expression of a truncated version of PDE4A5, which lacks the unique N-terminal targeting domain, does not affect long-term memory. Further, overexpression of the PDE4A1 isoform, which targets a different subset of signalosomes, leaves memory undisturbed. Fluorescence resonance energy transfer sensor-based cAMP measurements reveal that the full-length PDE4A5, in contrast to the truncated form, hampers forskolin-mediated increases in neuronal cAMP levels. Our study indicates that the unique N-terminal localization domain of PDE4A5 is essential for the targeting of specific cAMP-dependent signaling underlying synaptic plasticity and memory. The development of compounds to disrupt the compartmentalization of individual PDE4 isoforms by targeting their unique N-terminal domains may provide a fruitful approach to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling. SIGNIFICANCE STATEMENT Neurons exhibit localized signaling processes that enable biochemical cascades to be activated selectively in specific subcellular compartments. The phosphodiesterase 4 (PDE4) family coordinates the degradation of cAMP, leading to the local attenuation of cAMP-dependent signaling pathways. Sleep deprivation leads to increased hippocampal expression of the PDE4A5 isoform. Here, we explored whether PDE4A5 overexpression mimics behavioral and synaptic plasticity phenotypes associated with sleep deprivation. Viral expression of PDE4A5 in hippocampal neurons impairs long-term potentiation and attenuates the formation of hippocampus-dependent long-term memories. Our findings suggest that PDE4A5 is a molecular constraint on cognitive processes and may contribute to the development of novel therapeutic approaches to prevent cognitive deficits in neuropsychiatric and neurocognitive disorders that are associated with alterations in cAMP signaling.

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density.

Phosphodiesterases (PDEs) are a super family of 11 enzyme families responsible for the hydrolysis of the intracellular secondary messengers cyclic AMP (cAMP) and cyclic GMP (cGMP). PDE4, in particular, is highly expressed in brain regions involved with regulation of memory, anxiety, and depression, including the hippocampus, amygdala, and nucleus accumbens. Senescence has been shown to result in extreme dysregulation of the cAMP pathway in various brain regions. Thus, as a critical controller of intracellular cAMP levels, PDE4 may be a potential target for the treatment of senescence-related cognitive disorders, which could be pathological and/or non-pathological in origin. While there is great potential in the development of novel PDE4 inhibitors for treatment of senescent-cognition impairment, there are also currently many pitfalls that need to be overcome. PDE4 has four subfamilies (PDE4A, B, C, and D) that are differentially expressed throughout the brain and body, as well as at least 25 splice variants derived from alternative splicing and multiple promoter sites. PDE4 subtypes have been shown to have differential effects on behavior, and cAMP itself has also been shown to play a contrasting role in behavior in different brain regions. This review will focus on what is currently understood about PDE4 in aging, the potential for PDE4 modulation as a cognitive therapy, and current pitfalls and limitations that need to be overcome in the PDE4 field. Overall, furthering our understanding of this incredibly complex pathway may one day assist with the development of novel therapeutics for both pathological and non-pathological cognitive disorders associated with senescence.

Cognitive disorders such as depression, anxiety, and senescent-induced memory loss are a growing pandemic in the world. Anxiety is the most common psychiatric disorder in America, affecting upwards of 50 million people a year; depression has a lifetime prevalence of 20% of the population, and it's predicted pathological memory disorders such as Alzheimer's disease (AD) will reach exponential levels by the year 2050. While there are treatments for anxiety and depression, far less success has been reached with therapeutics for AD. Phosphodiesterases (PDEs) may be a potential novel target for future therapeutics aimed at combatting these psychiatric illnesses and neurodegenerative diseases. PDEs are a "super family" of 11 smaller enzyme families expressed throughout the body that degrade the cyclic nucleotides cAMP and/or cGMP, essentially acting as an off switch for intracellular cAMP and/or cGMP signaling. In particular, one member of this family termed PDE4 is highly expressed in regions of the brain that may play a role in these psychiatric disorders such as the prefrontal cortex (PFC), hippocampus, amygdala, and striatum. PDE4 has four subtypes (A, B, C, and D), of which only PDE4C is not highly expressed in the brain. It has been found through the use of genetic manipulation that PDE4D is highly involved with memory and depressive-like behavior, and PDE4B is involved with anxiety and release of inflammatory factors from immune cells; however, the functional role that PDE4A plays in behavior was not known. The purpose of this dissertation was to characterize the functional role of PDE4A in behavior through the use of PDE4A KO mice, and a battery of behavioral and biochemical tests. We found that PDE4A KO mice displayed a strong anxiogenic profile, and a prolonged release of corticosterone in response to a stressor. In addition, they also displayed enhanced emotional memory. PDE4A KO had no effect on depressive-like behavior, and decreased the training latency in the Morris Water Maze. PDE4A KO mice were also obese which was not due to hyperphagia or decreased locomotor activity. It was found that PDE4A KO decreased the levels of the major metabolic hormone T3. These results suggest that with further characterization, PDE4A may be a novel target in the future for anxiety or emotional memory disorders, as well as obesity.

Phosphodiesterases (PDEs) are a super family of enzymes responsible for the halting of intracellular cyclic nucleotide signaling and may represent novel therapeutic targets for treatment of cognitive disorders. PDE4 is of considerable interest to cognitive research because it is highly expressed in the brain, particularly in the cognition-related brain regions. Recently, the functional role of PDE4B and PDE4D, two of the four PDE4 subtypes (PDE4A, B, C, and D), in behavior has begun to be identified; however, the role of PDE4A in the regulation of behavior is still unknown.

It is well known that alongside senescence there is a gradual decline in cognitive ability, most noticeably certain kinds of memory such as working, episodic, spatial, and long term memory. However, until recently, not much has been known regarding the specific mechanisms responsible for the decline in cognitive ability with age. Over the past decades, researchers have become more interested in cAMP signaling, and its downstream transcription factor cAMP response element binding protein (CREB) in the context of senescence. However, there is still a lack of understanding on what ultimately causes the cognitive deficits observed with senescence. This review will focus on the changes in intracellular signaling in the brain, more specifically, alterations in cAMP/CREB signaling in aging. In addition, the downstream effects of altered cAMP signaling on cognitive ability with age will be further discussed. Overall, understanding the senescent-related changes that occur in cAMP/CREB signaling could be important for the development of novel drug targets for both healthy aging, and pathological aging such as Alzheimer's disease.

Sigma (σ) receptors have recently been identified as potential targets for the development of novel therapeutics aimed at mitigating the effects of methamphetamine. Particularly, σ receptors are believed to mitigate some of the neurotoxic effects of methamphetamine through modulation of dopamine, dopamine transporters and body temperature. Furthermore, recent evidence suggests that targeting σ receptors may prevent cognitive impairments produced by methamphetamine. In the present study, an optimized σ receptor antagonist, AZ66, was evaluated against methamphetamine-induced neurotoxicity and cognitive dysfunction. AZ66 was found to be highly selective for σ receptors compared to 64 other sites tested. Pretreatment of male, Swiss Webster mice with i.p. dosing of AZ66 significantly attenuated methamphetamine-induced striatal dopamine depletions, striatal dopamine transporter reductions and hyperthermia. Additionally, neurotoxic dosing with methamphetamine caused significant memory impairment in the object recognition test, which was attenuated when animals were pretreated with AZ66; similar trends were observed in the step-through passive avoidance test. Taken together, these results suggest that targeting σ receptors may provide neuroprotection against the neurotoxicity and cognitive impairments produced by methamphetamine.

RATIONALE:Cyclic AMP (cAMP)-protein kinase A signaling has been implicated in the regulation of ethanol consumption. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cAMP and plays a critical role in controlling intracellular cAMP levels in the brain. However, the role of PDE4 in ethanol consumption remains unknown.OBJECTIVE:The objective of this study is to examine whether PDE4 was involved in regulating ethanol intake.METHODS:The two-bottle choice paradigm was used to assess intake of ethanol, sucrose, and quinine in C57BL/6J mice treated with the selective PDE4 inhibitor rolipram or Ro 20-1724; locomotor activity was also monitored using the open-field test in mice treated with rolipram.RESULTS:Administration (i.p.) of either rolipram (0.25 and 0.5 mg/kg) or Ro 20-1724 (10 mg/kg) reduced ethanol intake and preference by 60-80%, but did not alter total fluid intake. In contrast, rolipram even at the higher dose of 0.5 mg/kg was not able to affect intake of sucrose or quinine, alcohol-induced sedation, or blood ethanol elimination. At 0.5 mg/kg, rolipram did decrease locomotor activity, but the effect only lasted for approximately 40 min, which did not likely affect behavior of ethanol drinking.CONCLUSIONS:These results suggest that PDE4 is a novel target for drugs that reduce ethanol intake; PDE4 inhibitors may be used for treatment of alcohol dependence.

Phosphodiesterases (PDEs) comprise a group of 11 families of enzymes that play a significant role in the regulation of intracellular signaling. Of particular interest to the CNS is PDE4 (comprised of four subtypes A, B, C and D) due to its high expression in the brain. While the examination of PDE4B and PDE4D knockout mice has begun to elucidate their roles in CNS function, the role of PDE4As remains largely unknown. The purpose of this study was to analyze the behavioral phenotype of PDE4A knockout mice, in particular as it relates to memory, anxiety, and depression. Using a battery of behavioral paradigms, including passive avoidance, water‐maze, forced‐swim, tail‐suspension, elevated plus‐maze, light dark transition, and holeboard tests, we found that PDE4A knockout mice displayed enhanced memory in the passive avoidance test, but not the water‐maze test; the mice also exhibited anxiogenic‐like behavior, but no significant changes in the forced‐swim or tail‐suspension tests. These results suggest that PDE4A may play a significant role in mediating memory and anxiety, but not depression related behavior.

Studies have shown that depression may be either a risk factor for Alzheimer's disease (AD) or an early symptom of AD. However, it is not known whether beta amyloid peptide 1–42 (Abeta42), which is mainly responsible for memory loss in AD, plays a role in depression associated with AD. Phosphodiesterase‐4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP, is involved in the mediation of antidepressant activity and memory. We examined the effects of Abeta42 on behavior in the forced‐swim and tail‐suspension tests in mice. Abeta42 (0.1, 0.4, and 1.6 μg/side), microinfused into bilateral dentate gyri of the mouse hippocampus, increased immobility in a dose‐dependent manner in both tests; it also decreased hippocampal neurogenesis, which is associated with depression. Interestingly, Abeta42 (0.4 μg/side)‐induced depressive‐like effects and decreases in neurogenesis were reversed by deficiency of PDE4D, one of the four PDE4 subtypes. These results suggest that Abeta42 may be an important mediator for depression in AD; disruption of PDE4D appears to be an effective approach to treatment of AD‐associated depression.

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Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study